Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism
Maria Jesus Iglesias
(1, 2, 3)
,
Laura Sanchez-Rivera
(1)
,
Manal Ibrahim-Kosta
(4, 5)
,
Clément Naudin
(1, 3)
,
Gaëlle Munsch
(6)
,
Louisa Goumidi
(4, 5)
,
Maria Farm
(7)
,
Philip M. Smith
(8)
,
Florian Thibord
(9, 10)
,
Julia Barbara Kral-Pointner
(11)
,
Mun-Gwan Hong
(1)
,
Pierre Suchon
(4, 5)
,
Marine Germain
(6)
,
Waltraud Schottmaier
(11)
,
Philip Dusart
(1, 3)
,
Anne Boland
(12)
,
David Kotol
(1)
,
Frederik Edfors
(1)
,
Mine Koprulu
(13)
,
Maik Pietzner
(13, 14, 15)
,
Claudia Langenberg
(13, 14, 15)
,
Scott M. Damrauer
(16)
,
Andrew D. Johnson
(9, 10)
,
Derek M. Klarin
(17, 18)
,
Nicholas Smith
(19, 20, 21)
,
David M. Smadja
(22, 23)
,
Margareta Holmstrom
(24)
,
Maria Magnusson
(7, 24)
,
Angela Silveira
(7, 24)
,
Mathias Uhlen
(1)
,
Thomas Renne
(25, 26, 27)
,
Angel Martinez-Perez
(28)
,
Joseph Emmerich
(29)
,
Jean-François Deleuze
(12, 30)
,
Jovan Antovic
(7, 24)
,
Jose Manuel Soria Fernandez
(28)
,
Alice Assinger
(11)
,
Jochen M. Schwenk
(1)
,
Joan Carles Souto Andres
(28)
,
Pierre-Emmanuel Morange
(4, 5)
,
Lynn Marie Butler
(1, 3, 7, 24)
,
David-Alexandre Tregouet
(6)
,
Jacob Odeberg
(1, 2, 3, 7, 24)
1
Science for Life Laboratory [Solna]
2 UNN - University Hospital of North Norway [Tromsø]
3 UiT - The Arctic University of Norway [Tromsø, Norway]
4 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
5 APHM - Assistance Publique - Hôpitaux de Marseille
6 BPH - Bordeaux population health
7 Karolinska Institute
8 KUH - Karolinska University Hospital [Solna, Sweden]
9 NHLBI - National Heart, Lung, and Blood Institute [Bethesda]
10 Framingham Heart Study
11 Medizinische Universität Wien = Medical University of Vienna
12 CNRGH - Centre National de Recherche en Génomique Humaine
13 CAM - University of Cambridge [UK]
14 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
15 QMUL - Queen Mary University of London
16 Perelman School of Medicine
17 Veterans Affairs Palo Alto Healthcare System
18 Stanford University
19 University of Washington [Seattle]
20 KPWHRI - Kaiser Permanente Washington Health Research Institute [Seattle]
21 Seattle Epidemiologic Research and Information Center [Seattle]
22 HEGP - Hôpital Européen Georges Pompidou [APHP]
23 IThEM - U1140 - Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis
24 Karolinska University Hospital [Stockholm]
25 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
26 University Medical Center of the Johannes Gutenberg-University Mainz
27 RCSI - Royal College of Surgeons in Ireland
28 Hospital de la Santa Creu i Sant Pau
29 CRESS (U1153 / UMR_A 1125) - Centre for Research in Epidemiology and Statistics | Centre de Recherche Épidémiologie et Statistiques
30 CEPH - Centre d'Etude du Polymorphisme Humain
2 UNN - University Hospital of North Norway [Tromsø]
3 UiT - The Arctic University of Norway [Tromsø, Norway]
4 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
5 APHM - Assistance Publique - Hôpitaux de Marseille
6 BPH - Bordeaux population health
7 Karolinska Institute
8 KUH - Karolinska University Hospital [Solna, Sweden]
9 NHLBI - National Heart, Lung, and Blood Institute [Bethesda]
10 Framingham Heart Study
11 Medizinische Universität Wien = Medical University of Vienna
12 CNRGH - Centre National de Recherche en Génomique Humaine
13 CAM - University of Cambridge [UK]
14 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
15 QMUL - Queen Mary University of London
16 Perelman School of Medicine
17 Veterans Affairs Palo Alto Healthcare System
18 Stanford University
19 University of Washington [Seattle]
20 KPWHRI - Kaiser Permanente Washington Health Research Institute [Seattle]
21 Seattle Epidemiologic Research and Information Center [Seattle]
22 HEGP - Hôpital Européen Georges Pompidou [APHP]
23 IThEM - U1140 - Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis
24 Karolinska University Hospital [Stockholm]
25 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
26 University Medical Center of the Johannes Gutenberg-University Mainz
27 RCSI - Royal College of Surgeons in Ireland
28 Hospital de la Santa Creu i Sant Pau
29 CRESS (U1153 / UMR_A 1125) - Centre for Research in Epidemiology and Statistics | Centre de Recherche Épidémiologie et Statistiques
30 CEPH - Centre d'Etude du Polymorphisme Humain
Résumé
Venous thromboembolism (VTE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. Here we show, using proteomics profiling to screen plasma from patients with suspected acute VTE, and several case-control studies for VTE, how Complement Factor H Related 5 protein (CFHR5), a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker. In plasma, higher CFHR5 levels are associated with increased thrombin generation potential and recombinant CFHR5 enhanced platelet activation in vitro. GWAS analysis of ~52,000 participants identifies six loci associated with CFHR5 plasma levels, but Mendelian randomization do not demonstrate causality between CFHR5 and VTE. Our results indicate an important role for the regulation of the alternative pathway of complement activation in VTE and that CFHR5 represents a potential diagnostic and/or risk predictive plasma biomarker.
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